2-Amino-4,5-dihydropyridine derivatives and process for their preparation

ABSTRACT

2-Amino-4,5-dihydropyridines-3,5-dicarboxylates substituted by lower alkoxy or lower alkylthio in the 6-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester is a representative embodiment, are prepared through condensation of an aldehyde and a 3-aminoacrylate bearing an alkoxy or alkylthio group in the 3-position.

This is a division of application Ser. No. 336,481 filed Feb. 28, 1973,now U.S. Pat. No. 3,874,646.

The present invention pertains to 2-amino-4,5-dihydropyridinederivatives, to processes for their production and use and topharmaceutical compositions containing such compounds and useful asantihypertensive agents and coronary vessel dilators.

In particular, the present invention pertains to compounds of theformula: ##SPC1##

Wherein

R is hydrogen; lower alkyl; lower alkenyl; lower alkynyl; phenyl;substituted phenyl in which the substituents are one to three membersselected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy),lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio or phenyl;naphthyl; or a heterocyclic ring selected from the group consisting ofquinolyl, isoquinolyl, pyridyl, thenyl, furyl and pyrryl, sidheterocyclic ring being unsubstituted or substituted by one or twomembers selected from the group consisting of lower alkyl, lower alkoxyand halogeno;

EACH OF R¹ and R², taken independently of the other, is lower alkyl,lower alkenyl or lower alkynyl; and

X is oxygen or sulfur.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms. Representative ofsuch lower alkyl groups are thus methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopentyl,tert. pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, allyl, isopropenyl,2-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl,4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl,4-pentynyl, and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through an ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example, methylthio, ethylthio, propylthio, isopropylthio,butylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting an aldehyde of the formula:

    RCHO

wherein R is as herein defined, with a 3-alkoxy- or3-alkylthio-3-aminoacrylate of the formula: ##STR1## in which R¹, R² andX are as herein defined. The condensation proceeds smoothly in goodyields simply by heating the two components, generally in the presenceof an inert organic solvent such as methanol, ethanol, propanol andsimilar alkanols, ethers such as dioxane and diethyl ether, glacialacetic acid, pyridine, dimethyformamide, dimethylsulfoxide,acetonitrile, and the like. The reaction is conducted at temperatures offrom 20° to 250° C, conveniently at the boiling point of the solvent,and while elevated pressure may be utilized, normal atmospheric pressureis generally satisfactory. The acrylate reactant is generally employedin about a two-fold molar excess.

It is rather surprising that the above described condensation producesthe desired compounds in such good yields and which such high puritysince it is known that an aldehyde condenses with an amino crotonic acidester to yield a 1,4-dihydropyridine (Cook et al., J. Chem. Soc. 1943,413). This is particularly true since it would be expected that the3-aminoacrylate reactant, which can be considered as an imino orthioimino ether, would yield the 2,6-dialkoxy-1,4-dihydropyridinederivative, Cope, J.A.C.S., 67 1017 (1945).

Many of the aldehydes utilized as one of the reactants are known to theart and the others can either be generated in situ as herein describedor prepared according to methods well known to the art, see for exampleOrg. Reactions VIII, 218 et seq. (1954). Typical of this reactant arethe following compounds:

formaldehyde,

acetaldehyde,

propionaldehyde,

isobutyraldehyde,

cyclopentaldehyde,

cyclohexanaldehyde,

acrolein,

cyclohex-3-enaldehyde,

benzaldehyde,

2-, 3- and 4-methylbenzaldehyde,

2-, 3- and 4-methoxybenzaldehyde,

3,4 and 5-trimethoxybenzaldehyde,

2-isopropoxybenzaldehyde,

2-, 3- and 4-chlorobenzaldehyde,

2-, 3- and 4-bromobenzaldehyde,

2-, 3- and 4-fluorobenzaldehyde,

2,4- and 2,6-dichlorobenzaldehyde,

2,4- and 2,3-dimethylbenzaldehyde,

2-, 3- and 4-nitrobenzaldehyde,

2,6-and 3,5-dinitrobenzaldehyde,

2-nitro-6-bromobenzaldehyde,

2-nitro-3-methoxy-6-chlorobenzaldehyde,

2-nitro-4-chlorobenzaldehyde,

2-nitro-4-methoxybenzaldehyde,

2-, 3- and 4-trifluoromethylbenzaldehyde,

2-carbethoxybenzaldehyde,

3-carbomethoxybenzaldehyde,

4-carbobutoxybenzaldehyde,

3-nitro-4-carbethoxybenzaldehyde-4-carboxylic acid ethyl ester,

α,β- and γ-pyridinaldehyde,

6-methylpyridin-2-aldehyde,

pyrimidin-5-aldehyde,

4,6-dimethoxypyrimidin-5-aldehyde,

2-, 3- and 4-cyanobenzaldehyde,

2-methylmercaptobenzaldehyde,

4-methylmercaptobenzaldehyde,

2-methylsulphonylbenzaldehyde,

1- and 2-naphthaldehyde,

5-bromo-1-naphthaldehyde,

2-ethoxy-1-naphthaldehyde,

4-methyl-1-naphthaldehyde,

quinolin-2-, 3-, 4-, 5-, 6-, 7- and 8-aldehyde,

isoquinolin-1,3,4-aldehyde,

furan-2-aldehyde,

thiophen-2-aldehyde and

pyrrol-2-aldehyde.

The 3-substituted 3-aminoacrylate reactants are similarly known or canbe readily produced according to known methods, see for example Cope,J.A.C.S., 67, 1017 (1945). Typical of these reactants are the following:

3-amino-3-methoxyacrylic acid methyl ester,

3-amino-3-methoxyacrylic acid ethyl ester,

3-amino-3-methoxyacrylic acid propyl ester,

3-amino-3-ethoxyacrylic acid methyl ester,

3-amino-3-ethoxyacrylic acid ethyl ester,

3-amino-3-ethoxyacrylic acid isopropyl ester,

3-amino-3-propoxyacrylic acid ethyl ester,

3-amino-3-isopropoxyacrylic acid ethyl ester,

3-amino-3-isopropoxyacrylic acid n-propyl ester,

3-amino-3-ethoxyacrylic acid cyclohexyl ester,

3-amino-3-ethoxyacrylic acid β-methoxyethyl ester,

3-amino-3-methylmercaptoacrylic acid ethyl ester,

3-amino-3-ethylmercaptoacrylic acid ethyl ester, and

3-amino-3-ethylmercaptoacrylic acid methyl ester.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a distinct and long lastingdilation of the coronary vessels which is intensified by a simultaneousnitrite-like effect of reducing the load on the heart. The effect onheart metabolism is thus one of energy saving. In addition, thecompounds lower the blood pressure of normotonic and hypertonic animalsand can thus be used as antihypertensive agents. These properties can beconveniently observed in well known laboratory models. Thus for examplea coronary vessel dilation effect can be observed by measuring theincrease in oxygen saturation in the coronary sinus in the narcotized,heart catheterized dog, as shown in the following table showing thedoses at which a clearly detectable rise is observed.

    ______________________________________                                           Compound         I.V. Dose (mg/kg)                                         ______________________________________                                        2-amino-4-methyl-6-ethoxy-4,5-                                                                    2 to 5                                                    dihydropyridine-3,5-dicarboxylic                                              acid diethyl ester                                                            2-amino-4-(2-nitrophenyl)-6-                                                                      3 to 5                                                    ethoxy-4,5-dihydropyridine-3,5-                                               dicarboxylic acid diethyl ester                                               2-amino-4-(3-nitrophenyl)-6-                                                                      2                                                         ethoxy-4,5-dihydropyridine-3,5-                                               dicarboxylic acid diethyl ester                                               ______________________________________                                    

The hypotensive activity of the present compounds can be observed bymeasuring the blood pressure of hypertensive rats followingadministration of the compounds. The following table demonstrates thedose which results in at least a 15 mm Hg reduction in blood pressure ofsuch animals:

    ______________________________________                                           Compound           I.V. Dose (mg/kg)                                       ______________________________________                                        2-amino-4-(2-nitrophenyl)-6-ethoxy-                                                                 10.0                                                    4,5-dihydropyridine-3,5-dicarboxylic                                          acid diethyl ester                                                            2-amino-4-(3-nitrophenyl)-6-ethoxy-                                                                  1.0                                                    4,5-dihydropyridine-3,5-dicarboxylic                                          acid diethyl ester                                                            2-amino-4-(4-chlorophenyl)-6-ethoxy-                                                                 3.1                                                    4,5-dihydropyridine-3,5-dicarboxylic                                          acid diethyl ester                                                            ______________________________________                                    

The toxicity of the compounds is also favorably low.

In addition to the effect on blood pressure and coronary vessels, thecompounds also lower the excitability of the stimulus formation andexcitation conduction system within the heart so that anantifibrillation action is observed at therapeutic doses. The tone ofthe smooth muscle of the vessels is also greatly reduced. Thisvascular-spasmolytic action can be observed in the entire vascularsystem as well as in more or less isolated and circumscribed vascularregions such as the central nervous system. In addition, a strongmuscular-spasmolytic action is manifested in the smooth muscle of thestomach, the intestinal tract, the urogenital tract and the respiratorysystem. Finally, there is some evidence that the compounds influence thecholesterol level and lipid level of the blood. These effects complementone another and the compounds are thus highly desirable aspharmaceutical agents to be used in the treatment of hypertension andconditions characterized by a constriction of the coronary bloodvessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95 to 0.5%, of at least one2-amino-4,5-dihydropyridine as herein defined in combination with apharmaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which isnon-toxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e. physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one-half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.05 to about 10 mg/kg, preferably 0.1 to 5 mg/kg, whenadministered parenterally and from about 1 to about 100 mg/kg,preferably 5 to 50 mg/kg, when administered orally. In some instances asufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solution, and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofthe invention since the subject matter regarded as the invention is setforth in the appended claims.

EXAMPLE 1 ##SPC2##

Boiling a solution of 2.4 g of acetaldehyde and 19 g of3-amino-3-ethoxyacrylic acid ethyl ester in 30 ml of alcohol for 8 hoursyields 2-amino-4-methyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 64° C (petroleum ether/ethylacetate). Yield: 57% of theory.

EXAMPLE 2 ##SPC3##

Upon boiling a solution of 5.3 g of benzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 30 ml of alcohol for 12hours, 2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 119° C (isopropanol) is obtained.Yield: 64% of theory.

EXAMPLE 3 ##SPC4##

Heating a solution of 7.6 g of 2-nitrobenzaldehyde and 15.9 of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 8 hoursyields2-amino-4-(2-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid ethyl ester of melting point 133°-4° C (isopropanol). Yield: 59% oftheory.

EXAMPLE 4 ##SPC5##

Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde and 14.5 g of3-amino-3-ethoxyacrylic acid methyl ester in 40 ml of alcohol for 6hours,2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester of melting point 163° C (isopropanol) is obtained.Yield: 71% of theory.

EXAMPLE 5 ##SPC6##

Upon heating a solution of 7.6 g of 3-nitrobenzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of isopropanol for 6hours,2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 129° (isopropanol) is obtained.Yield: 68% of theory.

EXAMPLE 6 ##SPC7##

Boiling a solution of 5.4 g of pyridin-2-aldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 8 hoursyields2-amino-4-(α-pyridyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 98° C (petroleum ether/ether). Yield: 55%of theory.

EXAMPLE 7 ##SPC8##

Upon heating a solution of 5.4 g of pyridin-4-aldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 12hours,2-amino-4-(γ-pyridyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 111° C (petroleum ether/ethyl acetate) isobtained. Yield: 72% of theory.

EXAMPLE 8 ##SPC9##

Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 40 ml of isopropanol for 8hours,2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 121° C is obtained. Yield: 76% oftheory.

EXAMPLE 9 ##SPC10##

Upon heating a solution of 7.1 g of 3-chlorobenzaldehyde and 14.5 g of3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 6hours,2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester of melting point 158° C (isopropanol) is obtained.Yield 78% of theory.

EXAMPLE 10 ##SPC11##

Boiling a solution of 7.1 g of 4-chlorobenzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 8 hoursyields2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 130°-132° C (ethyl acetate/petroleumether). Yield: 56% of theory.

EXAMPLE 11 ##SPC12##

Heating a solution of 6.3 g of 2-fluorobenzaldehyde and 14.5 g of3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 8hours yields2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester of melting point 180° C (isopropanol). Yield: 59% oftheory.

EXAMPLE 12 ##SPC13##

Upon boiling a solution of 8.8 g of 2,4-dichlorobenzaldehyde and 15.9 gof 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6hours,2-amino-4-(2,4-dichlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 98° C (ethyl acetate/ petroleumether) is obtained. Yield: 68% of theory.

EXAMPLE 13 ##SPC14##

Upon heating a solution of 9.3 g of 3-nitro-6-chlorobenzaldehyde and15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml ofisopropanol for 6 hours,2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 136°-37° C (isopropanol) isobtained. Yield: 65% of theory.

EXAMPLE 14 ##SPC15##

Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6hours,2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 119° C (ethyl acetate/petroleumether) is obtained. Yield: 47% of theory.

EXAMPLE 15 ##SPC16##

Boiling a solution of 6.5 g of 3-cyanobenzaldehyde and 15.9 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of ethanol for 8 hoursyields2-amino-4-(3-cyanophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 159° C (isopropanol). Yield: 73% oftheory.

EXAMPLE 16 ##SPC17##

Upon heating a solution of 4.8 g of furan-2-aldehyde and 15.9 g of3-amino-3-ethoxy-acrylic acid ethyl ester in 50 ml of alcohol for 8hours, 2-amino-4-(2-furyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 110° C (isopropanol) is obtained.Yield: 62% of theory.

EXAMPLE 17 ##SPC18##

Heating a solution of 6.1 g of 3-nitrobenzaldehyde and 13.9 g of3-amino-3-ethoxyacrylic acid isopropyl ester in 100 ml of ethanol for 8hours yields2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester of melting point 130° C (ether/petroleum ether).Yield: 45% of theory.

EXAMPLE 18 ##SPC19##

Heating a solution of 7.6 g of 4-methylmercaptobenzaldehyde and 15.9 gof 3-amino-3-ethoxyacrylic acid ethyl ester in 100 ml of ethanol for 8hours yields2-amino-6-ethoxy-4-(4-methylmercaptophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 132° C (isopropanol). Yield: 52% oftheory.

EXAMPLE 19 ##SPC20##

Upon heating of a solution of 8.9 g of 3-carbethoxybenzaldehyde and 15.9g of 3-amino-4-ethoxyacrylic acid ethyl ester in 50 ml of ethanol for 8hours,2-amino-4-(3-carbethoxyphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of m.p. 87° C (isopropanol) is obtained. Yield: 56%of theory.

EXAMPLE 20 ##SPC21##

Upon boiling of a solution of 9.1 g of biphenyl-4-aldehyde and 1.5 g of3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of ethanol for 8hours,2-amino-4-(4-biphenylyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of m.p. 145° C (isopropanol) is obtained. Yield: 48%of theory.

EXAMPLE 21 ##SPC22##

Upon boiling a solution of 6.5 g of 3-cyanobenzaldehyde and 17.5 g of3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for5 hours,2-amino-4-(3-cyanophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 153° C (isopropanol) is obtained.Yield: 38% of theory.

EXAMPLE 22 ##SPC23##

Upon heating a solution of 7.6 g of 3-nitrobenzaldehyde and 17.5 g of3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for6 hours,2-amino-4-(3-nitrophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 187° C (isopropanol) is obtained.Yield: 44% theory.

EXAMPLE 23 ##SPC24##

Upon boiling a solution of 5.3 g of pyridine-4-aldehyde and 17.5 g of3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for5 hours,2-amino-4-(4-pyridyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 156° C is obtained. Yield: 47% oftheory.

EXAMPLE 24 ##SPC25##

Upon heating a solution of 15.1 g of 3-amino-3-methylmercaptoacrylicacid ethyl ester and 7.6 g of 3-nitrobenzaldehyde in 100 ml of ethanolfor 5 hours,2-amino-4-(3-nitrophenyl)-6-methylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 144° C (isopropanol) is obtained.Yield: 39% of theory.

EXAMPLE 25 ##SPC26##

Upon heating of a solution of 8.7 g of 2-trifluoromethylbenzaldehyde and15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 100 ml ethanol for8 hours,2-amino-4-(2-trifluoromethylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of m.p. 116° C (ether) is obtained. Yield: 51% oftheory.

What is claimed is:
 1. A pharmaceutical composition for effectingcoronary vessel dilation in humans and animals and for treatinghypertension in humans and animals which comprises an effective coronaryvessel dilating amount or an effective antihypertensive amount of acompound of the formula: ##SPC27##wherein R is hydrogen; lower alkyl;phenyl; substituted phenyl in which the substituents are one to threemembers selected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy),lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio and phenyl; ornaphthyl; each of R¹ and R², taken independently of the other, is loweralkyl, lower alkenyl or lower alkynyl; and X is oxygen or sulfur;incombination with a pharmaceutically acceptable non-toxic inert diluentor carrier.
 2. A composition according to claim 1 wherein R¹ and R² arelower alkyl.
 3. A composition according to claim 2 wherein R isnaphthyl; phenyl; phenyl substituted with from one to three substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy),lower alkylsulfonyl, lower alkylsulfinyl and lower alkylthio; orbiphenyl.
 4. A composition according to claim 1 where in the compound is2-amino-4-methyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 5. A composition according to claim 1 where in thecompound is2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 6. A composition according to claim 1 where in thecompound is2-amino-4-(2-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid ethyl ester.
 7. A composition according to claim 1 where in thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 8. A composition according to claim 1 where in thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 9. A composition according to claim 1 where in thecompound is2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 10. A composition according to claim 1 where in thecompound is2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 11. A composition according to claim 1 where in thecompound is2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 12. A composition according to claim 1 where in thecompound is2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 13. A composition according to claim 1 where in thecompound is2-amino-4-(2,4-dichlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 14. A composition according to claim 1 where in thecompound is2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 15. A composition according to claim 1 where in thecompound is2-amino-4(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 16. A composition according to claim 1 where in thecompound is2-amino-4-(3-cyanophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 17. A composition according to claim 1 where in thecompound is2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester.
 18. A composition according to claim 1 where inthe compound is2-amino-6-ethoxy-4-(4-methylmercaptophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid ester.
 19. A composition according to claim 1 where in the compoundis2-amino-4-(3-ethoxycarbonylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 20. A composition according to claim 1 where in thecompound is2-amino-4-(4-biphenylyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 21. A composition according to claim 1 where in thecompound is2-amino-4-(3-cyanophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 22. A composition according to claim 1 where in thecompound is2-amino-4-(3-nitrophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 23. A composition according to claim 1 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-methylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 24. A composition according to claim 1 wherein thecompound is2-amino-4-(2-trifluoromethylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 25. A composition according to claim 1 wherein R islower alkyl, phenyl, phenyl substituted by lower alkyl, chlorine,fluorine, nitro, cyano, trifluoromethyl, carbo(lower alkoxy), loweralkylthio, phenyl, dichlorine or chlorine and nitro; R¹ is methyl, ethylor propyl; and R² is ethyl.
 26. A composition according to claim 1 inoral administration form.
 27. A composition according to claim 1 inparenteral administration form.
 28. A composition according to claim 27in a form suitable for intravenous administration.
 29. A method ofeffecting coronary vessel dilation in humans and animals which comprisesadministering to said human or animal an effective coronary vesseldilating amount of a compound of the formula: ##SPC28##wherein R ishydrogen; lower alkyl; phenyl; substituted phenyl in which thesubstituents are one to three members selected from the group consistingof lower alkyl, lower alkoxy, halogeno, nitro, cyano, trifluoromethyl,azido, carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl,lower alkylthio and phenyl; or naphthyl; each of R¹ and R², takenindependently of the other, is lower alkyl, lower alkenyl or loweralkynyl; and X is oxygen or sulfur.
 30. A method according to claim 29wherein R¹ and R² are lower alkyl.
 31. A method according to claim 29wherein R is naphthyl; phenyl; phenyl substituted with from one to threesubstituents selected from the group consisting of lower alkyl, loweralkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(loweralkoxy), lower alkylsulfonyl, lower alkylsulfinyl and lower alkylthio;or biphenyl.
 32. A method according to claim 29 wherein theadministration is oral.
 33. A method according to claim 29 wherein theadministration is parenteral.
 34. A method according to claim 29 whereinthe administration is intravenous.
 35. A method according to claim 29wherein the compound is2-amino-4-methyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 36. A method according to claim 29 wherein the compoundis 2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 37. A method according to claim 29 wherein the compoundis2-amino-4-(2-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid ethyl ester.
 38. A method according to claim 29 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 39. A method according to claim 29 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 40. A method according to claim 29 wherein thecompound is 2-amino-4-(3-chlorophenyl)6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
 41. Amethod according to claim 29 wherein the compound is2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 42. A method according to claim 29 wherein thecompound is2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 43. A method according to claim 29 wherein thecomound is2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 44. A method according to claim 29 wherein thecompound is2-amino-4-(2,4-dichlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 45. A method according to claim 29 wherein thecompound is2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 46. A method according to claim 29 wherein thecompound is2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 47. A method according to claim 29 wherein thecompound is2-amino-4-(3-cyanophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 48. A method according to claim 29 wherein thecompound is2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicaroboxylicacid diisopropyl ester.
 49. A method according to claim 29 wherein thecompound is2-amino-6-ethoxy-4-(4-methylmercaptophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid ester.
 50. A method according to claim 29 wherein the compound is2-amino-4-(3-ethoxycarbonylphenyl)-6-ethoxy-4,5-dihydro-pyridine-3,5-dicarboxylicacid diethyl ester.
 51. A method according to claim 29 wherein thecompound is2-amino-4-(4-biphenylyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 52. A method according to claim 29 wherein thecompound is2-amino-4-(3-cyanophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 53. A method according to claim 29 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 54. A method according to claim 29 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-methylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 55. A method according to claim 29 wherein thecompound is2-amino-4-(2-trifluoromethylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 56. A method of treating hypertension in humans andanimals which comprises administering to such said human or animal aneffective antihypertensive amount of a compound of the formula:##SPC29##wherein R is hydrogen; lower alkyl; phenyl; substituted phenylin which the substituents are one to three members selected from thegroup consisting of lower alkyl, lower alkoxy, halogeno, nitro, cyano,trifluoromethyl, azido, carbo(lower alkoxy), lower alkylsulfonyl, loweralkylsulfinyl, lower alkylthio and phenyl; or naphthyl; each of R¹ andR², taken independently of the other, is lower alkyl, lower alkenyl orlower alkynyl; and X is oxygen or sulfur.
 57. A method according toclaim 56 wherein R¹ and R² are lower alkyl.
 58. A method according toclaim 56 wherein R is naphthyl; phenyl; phenyl substituted with from oneto three substituents selected from the group consisting of lower alkyl,lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido,carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl and loweralkylthio; or biphenyl.
 59. A method according to claim 56 wherein theadministration is oral.
 60. A method according to claim 56 wherein theadministration is parenteral.
 61. A method according to claim 56 whereinthe administration is intravenous.
 62. A method according to claim 56wherein the compound is2-amino-4-methyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 63. A method according to claim 56 wherein the compoundis 2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic aciddiethyl ester.
 64. A method according to claim 56 wherein the compoundis2-amino-4-(2-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid ethyl ester.
 65. A method according to claim 56 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 66. A method according to claim 56 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 67. A method according to claim 56 wherein thecompound is 2-amino-4-(3-chlorophenyl)6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
 68. Amethod according to claim 56 wherein the compound is2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 69. A method according to claim 56 wherein thecompound is2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 70. A method according to claim 56 wherein thecompound is2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid dimethyl ester.
 71. A method according to claim 56 wherein thecompound is2-amino-4-(2,4-dichlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 72. A method according to claim 56 wherein thecompound is2-amino-4-(3-nitro-6-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 73. A method according to claim 56 wherein thecompound is2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 74. A method according to claim 56 wherein thecompound is2-amino-4-(3-cyanophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 75. A method according to claim 56 wherein thecompound is2-amino-6-ethoxy-4-(3-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester.
 76. A method according to claim 56 wherein thecompound is2-amino-6-ethoxy-4-(4-methylmercaptophenyl)-4,5-dihydropyridine-3,5-dicarboxylicacid ester.
 77. a method according to claim 56 wherein the compound is2-amino-4-(3-ethoxycarbonylphenyl)-6-ethoxy-4,5-dihydro-pyridine-3,5-dicarboxylicacid diethyl ester.
 78. A method according to claim 56 wherein thecompound is2-amino-4-(4-biphenylyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 79. A method according to claim 56 wherein thecompound is2-amino-4-(3-cyanophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 80. A method according to claim 56 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 81. A method according to claim 56 wherein thecompound is2-amino-4-(3-nitrophenyl)-6-methylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.
 82. A method according to claim 56 wherein thecompound is2-amino-4-(2-trifluoromethylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester.